Abstract A101: Novel KRAS inhibitors suppress MAPK pathway signalling and display potent anti-proliferative activity across a broad range of KRAS mutant cell lines

Abstract

Abstract KRAS is the most frequently mutated oncogene across different cancer types. Redx Pharma are developing novel, orally bioavailable, small molecule inhibitors of KRAS. These compounds display activity against a broad spectrum of the most frequently occurring KRAS mutations whilst maintaining selectivity over NRAS and HRAS protein isoforms. Isoform selective multi-KRAS inhibitors were identified using biochemical SOS1-independent nucleotide exchange assays (NEA) and validated by surface plasmon resonance (SPR) spectroscopy. Compounds of interest were the further triaged using relevant cancer cell lines for inhibition of phospho-ERK (pERK) and anti-proliferative effects both in 2 and 3-dimensional assay formats. KRAS selective inhibitors retaining activity across a spectrum of mutations were identified, these compounds exhibit picomolar affinity for KRAS, translating into low nanomolar antiproliferative activity. As further confirmation of MAPK pathway inhibition, treatment of relevant cancer cell lines with Redx compounds resulted in suppression of DUSP6 and SPTY4 gene expression. Cellular washout experiments indicated sustained inhibition of pERK post washout of compounds consistent with high affinity compounds with extended residency time at KRAS. Optimisation towards KRAS inhibitors suitable for clinical evaluation is ongoing. Citation Format: Inder Bhamra, Helen Mason, Simon Woodcock, Katie Anderson, James Kelly, Grace Haydon, Manuela La Montagna, Megan Brierley, Emma Bishop, Ross Keeler, James Ryan, Paula Jackson, Helen Aylott, Kelvin Ho, Daniel Leng, Clifford Jones, Caroline Phillips. Novel KRAS inhibitors suppress MAPK pathway signalling and display potent anti-proliferative activity across a broad range of KRAS mutant cell lines [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A101.